Integrin α5β1 is a heterodimeric cell surface protein that binds fibronectin and is involved in cell attachment and angiogenesis. This heterodimer is made up of an α5 subunit and a β1 subunit. Integrin α5β1 is referred to as the “classic fibronectin receptor” that plays key roles in matrix adhesion, migration, proliferation, differentiation, and survival. Although several integrins bind to fibronectin (FN), α5β1 is selective for FN as it requires both peptide sequences on the ninth (PHSRN) and tenth (RODS) type III repeats of FN for ligand recognition and optimal interaction. (Danen et al. J. Biol. Chem. 270(37):21612-21618 (1995); Redick et al. J. Cell Biol. 149(2):521-527 (2000); Takagi et al. EMBO J. 22:4607-4615 (2003)). Integrin-mediated cell adhesion to FN can trigger calcium fluxes, activate tyrosine and serine/threonine protein kinases and inositol lipid metabolism, and regulate the activity of the Rho family of small GTPases that controls the actin cytoskeleton and cell cycle progression.
Expression of α5β1 is observed in most embryonic tissues, but the level diminishes after birth in a manner consistent with terminal cell differentiation (Muschler & Horwitz Development 113(1):327-337 (1991)). In wild type adult mice, expression is mainly in the vasculature and connective tissue, although low levels of the receptor are widely distributed. Expression of both α5β1 and FN are significantly and coordinately enhanced on blood vessels of human tumors and in growth factor and cytokine stimulated tissues. Angiogenic cytokines such as bFGF, VEGF, IL-8, TOE-beta, and TNF-α upregulate α5β1 expression on endothelial cells in-vitro and in-vivo, whereas these molecules are minimally expressed on normal human vessels and tissues (Kim et al. Am. J. Path. 156(4):1345-62 (2000); Enaida et al. Fukushima J. Med. Sci. 44(1):43-52 (1998); Klein et al. Mol. Biol. Cell 4(10):973-982 (1993)).
High levels of α5β1 expression are not limited to the vasculature, as tumor cells are also frequently observed to express α5β1 in many types of cancer. Tumor hypoxia has been associated with increased tumor α5β1 expression (Mousa et al. J. Cell. Biochem. 74:135-143 (1999)). Integrins are thought to be important for tumor intravasation into newly formed capillaries and extravasation to distant sites, leading to tumor spreading and metastatic disease. Altogether, the expression pattern of α5β1 is consistent with multiple roles in promoting cancer, by mediating both stromal and tumor cell activities. Various clinical studies have associated α5β1 upregulation on tumor cells with progression of human melanoma, oral squamous cell carcinoma, and B-cell leukemias (Jin & Varner, Br. J. Cancer 90:561-565 (2004); Danen et al. Histopathology 24(3):249-256 (1994); Shinohara et al., Am. J. Clin. Pathol. 111(1):75-88 (1999)).